Recent studies indicate that cannabinoids can produce antinociception, particularly in persistent pain conditions, through peripheral mechanisms. This is particularly interesting because targeting peripheral receptors for pain eliminates unwanted side effects associated with receptor activation if the central nervous system. Moreover, it has been suggested that cannabinoids may be more effective in conditions of persistent pain. In the proposed studies we will investigate the ability of cannabinoids to attenuate cancer pain. Cancer pain is a major problem for many patients and is often undermanaged. Using a model of cancer pain in mice in which sarcoma cells are implanted in and around the calcaneous bone, we will determine whether cannabinoids attenuate hyperalgesia when administered at the site of tumor growth (hind paw) and identify the receptor types involved through the use of receptor-selective agonists and antagonists. Mechanisms underlying peripheral cannabinoid antinociception will be investigated in electrophysiological and cellular studies. In Parallel of electrophysiological studies, we will determine if cannabinoids attenuate the sensitization of nociceptors that occurs during tumor growth. We will also investigate cellular events related to cannabinoid signaling that occur during tumor growth. We will determine whether cancer cells modify cannabinoid receptor expression and cannabinoid receptor signaling in primary afferent neurons.